Microalbuminuria as a predictor of a drop in glomerular filtration rate in subjects with non-insulin-dependent diabetes mellitus and hypertension.

UNLABELLED: Hypertension and non-insulin-dependent diabetes mellitus (NIDDM) are two major risk factors for end-stage renal failure. The value of microalbuminuria (urinary albumin excretion [UAE]: 30-300 mg/24 h) as an indicator of the glomerular filtration rate (GFR) is not known in these patients. METHODS: The relationships between microalbuminuria and GFR in subjects with NIDDM and hypertension were studied cross-sectionally (Study I) and longitudinally (Study II). RESULTS: In study I, 205 NIDDM subjects with hypertension (151 with normoalbuminuria [UAE < 30 mg/24 h] and 54 with microalbuminuria) were studied. The GFR of subjects with normoalbuminuria (97 +/- 30 ml/min) (mean +/- SD), and microalbuminuria (97 +/- 27 ml/min; NS) were similar. Study II examined 51 of the subjects with normoalbuminuria and 21 with microalbuminuria 22 months (range 13-57) later. The GFR of subjects with microalbuminuria (-10 +/- 19 ml/min) declined more than in those with normoalbuminuria (+4 +/- 17 ml/min; Student's t-test: p = 0.0022). The predictive value of microalbuminuria for a drop in GFR was independent of the antihypertensive treatment used, the follow-up time, or changes in UAE. The only variable linked to GFR loss in subjects with microalbuminuria was an increase in diastolic blood pressure (p = 0.0298). CONCLUSION: Microalbuminuria is a risk factor for a drop in GRF in NIDDM subjects with hypertension, and a reduction in blood pressure is the only effective way to prevent a loss of GFR in subjects with microalbuminuria.

Contribution of genetic polymorphism in the renin-angiotensin system to the development of renal complications in insulin-dependent diabetes: Genetique de la Nephropathie Diabetique (GENEDIAB) study group.

Diabetic nephropathy is a glomerular disease due to uncontrolled diabetes and genetic factors. It can be caused by glomerular hypertension produced by capillary vasodilation, due to diabetes, against constitutional glomerular resistance. As angiotensin II increases glomerular pressure, we studied the relationship between genetic polymorphisms in the renin-angiotensin system-angiotensin I converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II, subtype 1, receptor-and the renal involvement of insulin-dependent diabetic subjects with proliferative retinopathy: those exposed to the risk of nephropathy due to diabetes. Of 494 subjects recruited in 17 centers in France and Belgium (GENEDIAB Study), 157 (32%) had no nephropathy, 104 (21%) incipient (microalbuminuria), 126 (25 %) established (proteinuria), and 107 (22%) advanced (plasma creatinine > or = 150 micromol/liter or renal replacement therapy) nephropathy. The severity of renal involvement was associated with ACE insertion/deletion (I/D) polymorphism: chi2 for trend 5.135, P = 0.023; adjusted odds ratio attributable to the D allele 1.889 (95% CI 1.209-2.952, P = 0.0052). Renal involvement was not directly linked to other polymorphisms. However, ACE I-D and AGT M235T polymorphisms interacted significantly (P = 0.0166): in subjects with ACE ID and DD genotypes, renal involvement increased from the AGT MM to TT genotypes. Thus, genetic determinants that affect renal angiotensin II and kinin productions are risk factors for the progression of glomerular disease in uncontrolled insulin-dependent diabetic patients.

1,25-Dihydroxyvitamin D3 regulates gamma 1 transpeptidase activity in rat brain.

gamma-Glutamyl transpeptidase (gamma-GT), primarily described as a kidney enzyme, is also expressed in several cell types of the central nervous system (CNS). It is involved in the glutathione cycle and in cysteine transport. Here we report that the specific activity of this enzyme is transiently increased in the rat brain, following a treatment with 1,25-dihydroxyvitamin D3 (1,25-D3), the active form of vitamin D. In vitro experiments showed that this positive regulatory effect does not affect endothelial cells of the brain microvessels, but does affect pericytes and parenchymal astrocytes. Changes in the specific activity of gamma-GT were not correlated with any important modification of brain amino acid concentrations. Since gamma-GT is though to participate in the scavenging of reactive oxygen species, these data suggest that 1,25-D3 could be an effector controlling detoxification processes in the brain.

Relationship between fat intake and glomerular filtration rate in normotensive insulin-dependent diabetic patients.

Glomerular hyperfiltration is a candidate marker for diabetic nephropathy in insulin-dependent diabetic patients since it can reflect elevated glomerular capillary pressure, a cause of glomerulosclerosis. We studied the potential contribution of several dietary components to glomerular hyperfiltration during a cross-sectional study of 110 consecutive normotensive, non-proteinuric insulin-dependent patients with respect to glomerular filtration rate (GFR) and food intake. GFR was measured using the 51Cr-EDTA plasma disappearance technique. Glomerular hyperfiltration was defined as GFR > 137 ml.min-1 1.73 m-2 (mean +2 SD of age-matched healthy controls). Food intake was recorded with a computer-assisted programme. Thirteen patients displaying glomerular hyperfiltration ingested more protein (1.60 +/- 37 vs 1.38 +/- 0.34 g.kg-1 body weight.day-1; p = 0.032) and more fat (1.70 +/- 0.54 vs 1.39 +/- 0.44 g.kg-1 body weight.day-1; p = 0.022) than other subjects, although their total energy intakes were similar. Univariate regression analysis showed that GFR was positively related to both protein (r = 0.28; p = 0.003) and fat (r = 0.25; p = 0.007) intakes and negatively related to age (r = -0.29; p = 0.002). Stepwise multivariate regression analysis indicated 2 independent determinants for GFR: age (F = 15.26) and fat intake (F = 13.15). Excess fat intake may contribute to glomerular hyperfiltration in insulin-dependent diabetes.

[Increase of activity of angiotensin-converting enzyme in insulin-dependent diabetic patients with permanent microalbuminuria]. / Elévation de l'activité de l'enzyme de conversion chez des diabétiques insulino-dépendants présentant une microalbuminurie permanente.

Angiotensin I Converting Enzyme (ACE), which is synthesized by vascular endothelial cells, can be elevated in some diabetic subjects. To study if serum ACE can be elevated in subjects with high risk for malignant microangiopathy, 34 normotensive type I, insulin-dependent diabetic subjects with persistent microalbuminuria (30-300 mg/24 h) were compared for serum ACE activity (Liebermann's method) with 30 normotensive, normoalbuminuric type I, insulin-dependent diabetic subjects of same age (33 +/- 15 (M +/- SD) vs 39 +/- 14 years), sex (13 F/21 M vs 15 F/15 M), stage of retinopathy (14 vs 16 nil/11 vs 7 background/6 vs 4 preproliferative/3 vs 3 proliferative), HbA1c (7.7 +/- .9 vs 8.2 +/- 1.0%). Serum ACE activity of diabetic subjects were also compared with 120 age and sex related healthy controls. Serum ACE activity was higher in type I, insulin-dependent diabetic subjects with microalbuminuria than in those with normoalbuminuria (406 +/- 114 vs 359 +/- 97 IU/l; p = 0.05), or in controls (307 +/- 95 IU/l; p = 0.0001). Normoalbuminuric subjects also had higher ACE activity than controls (p = 0.02). In diabetic subjects, serum ACE activity was not related to diabetes duration (r = 0.1; ns), stage of retinopathy (r = 0.06; ns), HbA1c (r = 0.02; ns), or to blood pressure (r = 0.03; ns), but was related to urinary albumin excretion (r = 0.28; p = 0.03) in diabetic subjects. However, stage of retinopathy was related to diabetes duration (r = 0.74; p = 0.0004) and to age (r = 0.42; p = 0.003) in these subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum lipids and urinary albumin excretion in non insulin-dependent diabetics.

The increase of urinary albumin excretion has a predictive value for cardiovascular disease in insulin-dependent and non insulin-dependent diabetics. To study the relationship between urinary albumin excretion and serum lipids, 380 non insulin-dependent diabetics, 40 to 75 yr old, with urinary albumin excretion from 0 to 200 mg/l, and normal serum creatinine (less than 150 mumol/l), were surveyed. Urinary albumin excretion, was related positively to age (r2 = 0.014; p = 0.02), to systolic blood pressure (r2 = 0.073, p = 0.0001) and diastolic blood pressure (r2 = 0.052, p = 0.0001); a negative correlation existed with HDL-cholesterol (r2 = 0.043, p = 0.0001) and Apoprotein A1 (r2 = 0.044, p = 0.0001). A stepwise regression analysis was performed and resulted in three independently contributing variables related to urinary albumin excretion: First systolic blood pressure (F = 36), second Apoprotein A1 (F 24), third hemoglobin A1C (F = 6). The presence of hypertension or insulin therapy did not modify these findings. In conclusion, serum lipid seems an important determinant of urinary albumin excretion in non insulin-dependent diabetics.

Predictive value of testing random urine sample to detect microalbuminuria in diabetic subjects during outpatient visit.

The predictive value of random urine sample during outpatient visit to predict persistent microalbuminuria was studied in 76 Type 1, insulin-dependent diabetic subjects, 61 Type 2, non-insulin-dependent diabetic subjects, and 72 Type 2, insulin-treated diabetic subjects. Seventy-six patients attended outpatient clinic during morning, and 133 during afternoon. Microalbuminuria was suspected if Urinary Albumin Excretion (UAE) exceeded 20 mg/l. All patients were hospitalized within 6 months following outpatient visit, and persistent microalbuminuria was assessed then if UAE was between 30 and 300 mg/24 h on 2-3 occasions in 3 urines samples. Of these 209 subjects eighty-three were also screened with Microbumintest (Ames-Bayer), a semi-quantitative method. Among the 209 subjects, 71 were positive both for microalbuminuria during outpatient visit and a persistent microalbuminuria during hospitalization: sensitivity 91.0%, specificity 83.2%, concordance 86.1%, and positive predictive value 76.3% (chi-squared test: 191; p less than 10(-4)). Data were not different for subjects examined on morning, or on afternoon. Among the 83 subjects also screened with Microbumintest, 22 displayed both a positive reaction and a persistent microalbuminuria: sensitivity 76%, specificity 81%, concordance 80%, and positive predictive value 69% (chi-squared test: 126; p less than 10(-4)). Both types of screening appeared equally effective during outpatient visit. Hence, a persistent microalbuminuria can be predicted during an outpatient visit in a diabetic clinic.

[Dissociation of hypotensive and renal hemodynamic effects of an angiotensin converting enzyme inhibitor in insulin-dependent diabetic patients with incipient nephropathy]. / Dissociation des effets hypotenseurs et hémodynamiques rénaux d'un inhibiteur de l'enzyme de conversion chez des diabétiques insulinodépendants avec néphropathie débutante.

The mechanism of action of angiotensin converting enzyme (ACE) inhibitors on urinary albumin excretion (UAE) in diabetics is controversial. In order to dissociate the hypotensive and intrarenal effects, 16 insulin-dependant diabetics with permanent microalbuminuria (30-300 mg/24 h) without hypertension were given Ramipril, a long acting ACE inhibitor, at hypotensive (treatment A 5 mg/day; N = 8) and at sub-hypotensive doses (treatment B, 1.25 mg/day; N = 8) over a 6 week period in parallel double-blind study. Blood pressure, UAE, glomerular filtration renal blood flow (continuous 125I-Iodothalamate + 131I-Hippurate infusion) and converting enzyme activity (Liebermann's method), before and after treatment. In treatment group A, the blood pressure fell from 133 +/- 5/79 +/- 4 (mean +/- SE) to 125 +/- 4/77 +/- 2 mmHg (p less than 0.05 for systolic blood pressure) whereas it remained stable in treatment group B (132 +/- 7/79 +/- 4 to 128 +/- 5/80 +/- 4 mmHg). The UAE decreased in both groups: group A from an average of 74 (40-198) to 47 (5-202) mg/24 h (p = 0.07; group B, from an average of 77 (50-136) to 19 (15-120) mg/24 h (p less than 0.005), as did ACE activity: group A from 332 +/- 44 to 163 +/- 33 iu/l (p less than 0.004), group B from 423 +/- 39 to 191 +/- 28 iu/l (p less than 10-4).(ABSTRACT TRUNCATED AT 250 WORDS)

Small doses of ramipril to reduce microalbuminuria in diabetic patients with incipient nephropathy independently of blood pressure changes.

The mechanism of action of angiotensin-converting enzyme (ACE) inhibitors on urinary albumin excretion (UAE) in diabetic patients remains controversial. Sixteen type 1, insulin-dependent diabetics with incipient nephropathy received ramipril, a long-acting ACE inhibitor, at hypotensive doses (treatment A: 5 mg/day, n = 8) or at nonhypotensive doses (treatment B: 1.25 mg/day, n = 8) during a 6-week, double-blind, parallel study to establish whether its antihypertensive effects could be dissociated from its local renal effects. Blood pressure, UAE, glomerular filtration rate (GFR), effective renal plasma flow (ERPF, constant [125I]iodothalamate + [131I]hippurate infusion), and ACE activity were measured before and after treatment. Blood pressure was lowered with treatment A but not with treatment B. UAE and ACE activity were reduced with both treatments. Baseline GFR and ERPF were not altered by either treatment. In the patient population as a whole, ACE inhibition correlated with a rise in ERPF and with a reduction in filtration fraction (GFR/ERPF), but not with the changes in blood pressure. Changes in UAE correlated with the changes in filtration fraction. It is concluded that renal hemodynamics may be modified by ramipril independently of blood pressure changes.

The distribution of elements in the tissues of Watanabe Heritable Hyperlipidemic Rabbits.

A deficiency or an excess of some elements in the diet is reported to modify the concentration of cholesterol in plasma, and, conversely, a reduction of cholesterol in the diet decreases zinc in plasma. We have studied the distribution of elements Na, K, Ca, Mg, Fe, Cu, Zn, S, P, and Mn in the tissues, plasma, heart, aorta, lung, liver, spleen, kidney, thymus, and brain of New Zealand White rabbits (NZW) and of Watanabe Heritable Hyperlipidemic rabbits (WHHL). The WHHL rabbits had a massive hypercholesterolemia (7.45 +/- 1.2 g/L) induced by a lack of liver low density lipoprotein receptors. The concentrations of elements in the tissues of the control NZW rabbits were very similar to those found in the normal rat. In WHHL, compared to NZW, besides the very important increase of total phosphorus in plasma explained by the augmentation of phospholipids, there was an increase of plasma copper (+44%) and zinc (+36%). The other noticeable changes were an increase of iron in heart (+19%), sulfur, and zinc in liver (+15% and +18%). The other changes observed in WHHL rabbits were, besides the increase of ceruloplasmin, the increase of vit E (+468%) and MDA (+62%). In conclusion, despite a massive increase of lipids in plasma, there was no major disturbance of element distribution in WHHL rabbits.